Nitroglycerin has been used for over 100 years in the treatment and control of a variety of cardiovascular disorders including angina pectoris, paroxysmal nocturnal dyspnea, acute biliary colic and, in recent years, it has been employed intravenously to combat intra-and postoperative hypertension associated with cardiovascular surgery. One of the most troublesome problems related to nitroglycerin use has been the tolerance development phenomenon. Although it has been the subject of considerable attention, tolerance mechanism(s) have remained undefined. This proposal addressed four potential explanations of resistance development; the first three focus on in vivo effects; namely, 1) the ability of nitroglycerin to oxidize sulfhydryl sites of vasodilator action, 2) the ability of nitroglycerin to increase free fatty acid levels which, in turn, may compete with the drug for nitroglycerin receptors and 3) a possible cooperative protein binding effect which may result in a reduction of free nitroglycerin levels upon successive dosing. The fourth approach is directed toward an extracorporeal mechanism that may be of unique importance in explaining the apparent tolerance that develops in patients receiving intravenous infusions of the drug. Nitroglycerin, and a variety of other drugs, are known to be lost from solution when stored in I.V. bags for even very short periods of time (minutes). This process will be quantitatively characterized using kinetic sorption theory and the procedures established should provide not only a model for predicting nitroglycerin loss in infusion bags but one that may be applicable to other drugs lost through the sorption process.